Interleukin 17 (IL17) plays a key role in mediating inflammatory and autoimmune diseases. A unique intracellular signaling domain termed 'SEFIR' was identified within all IL17 receptors (IL17Rs) and the adaptor protein, nuclear factor ?B (NF-?B) activator 1 (Act1). A key step in IL17 signaling is the recruitment of Act1 to IL17Rs via SEFIR mediated associations. As the largest among all IL17Rs, IL17RA is a key receptor involved in essentially all IL17 signaling and requires a unique structural module (SEFEX) that is composed of both SEFIR and a short flanking C-terminal extension. The structure and mechanism of SEFEX-mediated IL17RA signaling are not known. In this proposal, we aim for providing molecular details of SEFEX domain from IL17RA, and revealing the molecular principles by which SEFEX recruits Act1 for IL17RA intracellular signaling. Aim 1. Structural and functional studies on the SEFEX domain of IL17RA. Hypothesis: The intracellular signaling module of IL17RA is unique among all IL17 receptors, and contains the SEFIR and a C-terminal flanking fragment of about 100 a.a. The IL17RA SEFIR domain itself adopts a unique structure, compared to that from other IL17Rs and Act1. I) We will determine the crystal structure of IL17RA-SEFEX. II) We will map the functional residues on IL17RA SEFEX that are critical for interaction with Act1 and IL17-stimulated signaling. We will use mutagenesis, CO-IP, surface plasmon resonance, and cell-based IL17 signaling assays. Aim 2. Determine the mechanism by which IL17RA recruits Act1 by structural and functional studies. Hypothesis: Helix ?C in the SEFIR domains is a conserved structural motif involved in heterotypic SEFIR- SEFIR interactions. Therefore peptides derived from the ?C helix of Act1, IL17RB or IL17RA will be inhibitory for IL17/IL25 signaling. I) We will determine the molecular mechanism by which IL17RA recruits Act1 by structural biology. II) We will develop cell-permeable inhibitory peptides for inhibition of IL17 signaling. These studies offer an opportunity for uncovering novel approaches for modulating IL17 and IL25 signaling. Our objectives are the detailed characterizations of the unique signaling domain from IL17RA, which is the most commonly shared receptor for nearly all IL17 ligands signaling. The expected results will provide detailed structural information for advancing our understanding on the fundamental principles of IL17 receptor signaling. Our studies will provide a platform for designing selective inhibitors that may be further developed into new therapeutics against a number of inflammatory and autoimmune diseases.